Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract disease in infants and young children worldwide. It's responsible for approximately 90,000 admissions and $300 million in direct medical costs annually in the U.S. alone. In fact, nearly all children are infected by age 2 years. While most infected children present wi th mild upper respiratory tract symptoms, approximately 1 to 2% develop severe lower respiratory tract disease characterized by tachypnea, hyperinflation, crackles, and expiratory wheezing (i.e., bronchiolitis and pneumonia). However, RSV disease spans the extremes of age as it is also an important cause of outbreaks of respiratory disease in older adults over 65 years of age and in nursing homes and other institutionalized care settings. The overall goal of this project is to use Novavax's Virus- Like Particle (VLP) technology to develop a safe and efficacious RSV vaccine for the prevention of severe lower respiratory tract disease caused by (RSV) types A and B. Several candidates will be developed and evaluated. The primary candidate is anticipated to be a VLP containing the immunologically and structurally important fusion (F) and matrix (M) proteins of RSV produced in baculovirus-infected Spodoptera frugiperda (Sf9) cells. The Phase I specific aims are 1) to select chimeric RSV VLP candidate immunogens made using F0 from subtype A with or without Ga and Gb from RSV subtypes A and B, respectively. Recombinant chimeric RSV VLPs will be produced in insect or avian cell lines and purified using a process similar to what Novavax has developed for recombinant Influenza VLP vaccines, currently in clinical evaluation;2) purified VLPs will be characterized, and tested for sterility and purity;3) RSV VLP will be tested in mice following intramuscular immunization for induction of functional antibody and specific T-cell responses and protection against challenge with live RSV;4) the lead candidate will be further tested for efficacy and safety (i.e., lack of disease enhancement) in the bovine calf model. Novavax expects to continue development with a Phase II SBRI grant to support completion of process development and GMP manufacturing and testing a candidate RSV VLP vaccine for toxicology studies in preparation for clinical development. PUBLIC HEALTH RELEVANCE: Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract disease in infants and young children worldwide. RSV is also an important cause of outbreaks of respiratory disease in older adults over 65 years of age and in nursing homes and other institutionalized care settings. The overall goal of this project is to develop a safe and efficacious RSV vaccine for the prevention of severe lower respiratory tract disease.